BACKGROUND Diabetes is a risk factor for developing Alzheimer's disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aβ pathology and increased expression of glial activation markers in APPswe/PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. METHODS To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. RESULTS Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1β, and MCP-1) and pro-inflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aβ1-40, Aβ1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. CONCLUSIONS Altogether, our multiplexed analysis of cytokines shows that Alzheimer's and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aβ and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD.

中文翻译：

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β淀粉样蛋白和糖尿病病理共同刺激阿尔茨海默病小鼠模型中的细胞因子表达。


背景技术糖尿病是发生阿尔茨海默氏病（AD）的危险因素。然而，糖尿病促进 AD 病理的机制仍不清楚。糖尿病导致大脑发生多种分子变化，包括葡萄糖代谢失调和脑血管稳态丧失。尽管这些变化与 APPswe/PS1dE9 (APP/PS1) 小鼠中 Aβ 病理学增加和神经胶质激活标记物表达增加有关，但迄今为止，与糖尿病相关的神经炎症变化的特征仍然有限。方法 为了更全面地阐明可能驱动 AD 病理学的与糖尿病相关的神经炎症变化，我们将 APP/PS1 小鼠模型与高脂饮食（HFD，糖尿病前期模型）、2 型遗传 db/db 模型相结合糖尿病，或 1 型糖尿病的链脲佐菌素 (STZ) 模型。然后，我们使用多重免疫测定来量化细胞因子蛋白的皮质变化。结果我们的分析显示，与 db/db、HFD 或 STZ 模型相关的病理学导致多种细胞因子的上调，包括趋化因子（例如 MIP-1α、MIP-1β 和 MCP-1）和促炎细胞因子，包括IL-1α、IFN-γ和IL-3。此外，多变量偏最小二乘回归分析表明，组合的糖尿病-APP/PS1模型产生了与单独的每个糖尿病模型相关的细胞因子谱的协同增强的表达。最后，在 APP/PS1xdb/db 小鼠中，我们发现 Aβ1-40、Aβ1-42、葡萄糖和胰岛素的循环水平均与大脑中细胞因子的表达相关，表明外周变化与大脑病理之间存在密切关系。 结论 总而言之，我们对细胞因子的多重分析表明，阿尔茨海默病和糖尿病病理学协同增强了据报道与这两种疾病有关的细胞因子的分布。此外，由于许多已确定的细胞因子会促进神经元损伤、Aβ 和 tau 蛋白病理学以及血脑屏障的破坏，因此我们的数据表明神经炎症可能介导糖尿病对 AD 发病机制的影响。因此，针对神经炎症信号传导以及代谢控制的策略可能为干预糖尿病相关 AD 的发展提供有前景的策略。